Genetic Variant FGD1:p.Pro176_Leu177insArgGlyProHisProProProPro (chrX-54470714-T-TGGGGGGGGGGGGTGGGGCCCCCGG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_004463.3(FGD1):c.527_528insCCGGGGGCCCCACCCCCCCCCCCC(p.Pro176_Leu177insArgGlyProHisProProProPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P176P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 19)

Exomes 𝑓: 0.0000056 ( 0 hom. 0 hem. )

Consequence

FGD1
NM_004463.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.452

Publications

0 publications found

Variant links:

Genes affected

FGD1 (HGNC:3663): (FYVE, RhoGEF and PH domain containing 1) This gene encodes a protein that contains Dbl (DH) and pleckstrin (PH) homology domains and is similar to the Rho family of small GTP-binding proteins. The encoded protein specifically binds to the Rho family GTPase Cdc42Hs and can stimulate the GDP-GTP exchange of the isoprenylated form of Cdc42Hs. It also stimulates the mitogen activated protein kinase cascade leading to c-Jun kinase SAPK/JNK1 activation. Defects in this gene are the cause of the faciogenital dysplasia in Aarskog-Scott syndrome and a syndromatic form of X-linked cognitive disability. [provided by RefSeq, Jul 2017]

FGD1 Gene-Disease associations (from GenCC):

Aarskog-Scott syndrome, X-linked
Inheritance: AD, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

FGD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_004463.3.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004463.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	NM_004463.3	MANE Select	c.527_528insCCGGGGGCCCCACCCCCCCCCCCC	p.Pro176_Leu177insArgGlyProHisProProProPro	disruptive_inframe_insertion	Exon 3 of 18	NP_004454.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGD1	ENST00000375135.4	TSL:1 MANE Select	c.527_528insCCGGGGGCCCCACCCCCCCCCCCC	p.Pro176_Leu177insArgGlyProHisProProProPro	disruptive_inframe_insertion	Exon 3 of 18	ENSP00000364277.3	P98174
FGD1	ENST00000934021.1		c.527_528insCCGGGGGCCCCACCCCCCCCCCCC	p.Pro176_Leu177insArgGlyProHisProProProPro	disruptive_inframe_insertion	Exon 3 of 19	ENSP00000604080.1
FGD1	ENST00000934019.1		c.527_528insCCGGGGGCCCCACCCCCCCCCCCC	p.Pro176_Leu177insArgGlyProHisProProProPro	disruptive_inframe_insertion	Exon 3 of 18	ENSP00000604078.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000556

AC:

AN:

179921

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

37593

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

5667

American (AMR)

AF:

0.00

AC:

AN:

7068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4754

East Asian (EAS)

AF:

0.00

AC:

AN:

10156

South Asian (SAS)

AF:

0.00

AC:

AN:

9865

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13487

Middle Eastern (MID)

AF:

0.00

AC:

AN:

925

European-Non Finnish (NFE)

AF:

0.00000840

AC:

AN:

119081

Other (OTH)

AF:

0.00

AC:

AN:

8918

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.45

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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X-54470714-TGGGG-TGGGGGGGGGGGGTGGGGCCCCCGGGGGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over